HOST CELL INTERACTIONS BY PATHOGENIC BORRELIAE

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Borrelia burgdorferi is the causative agent of Lyme disease, and B. hermsii and B. turicatae are causative agents of tick-borne relapsing fever. Pathogen-host cell interactions are thought to be critical determinants of the site and severity of infection, and we have focused on Borrehae recognition of two classes of host cell molecules: (1) glycosaminoglycans (GAGs); and (2) integrins and their associated proteins. For B. burgdorferi, we found that differences in GAG recognition were associated with differences in host cell type-specific binding, and identified a surface protein, Bgp, that may be the major B. burgdorferi GAG receptor. This bacterium also recognizes the activation- dependent platelet integrin alphaIIbbeta3, and thereby selectively binds to activated (vs. resting) platelets. This integrin-binding activity is predicted to target the Lyme disease spirochete to the vessel wall at sites of platelet adherence, and could explain a salient feature of Lyme disease: vascular pathology of the arterial circulation. In our studies of relapsing fever spirochetes. high-level GAG- binding correlated with high-level growth in the bloodstream and a variable major protein. VspB, promoted attachment to GAGS. Additionally, to contrast to B. burgdorferi, B. hermsii bound and activated resting platelets. This contact-dependent platelet activation activity was apparently mediated by the integrin- associated platelet signaling molecule CD9. Relapsing fever spirochetes have also been shown to bind to erythrocytes, and we speculate that attachment of relapsing fever spirochetes to circulating blood cells such as platelets and erythrocytes could promote the retention and high level growth of the bacteria in the blood. Interaction of spirochetes with these two cell types could also contribute to two common manifestations of relapsing fever: anemia and thrombocytopenia. Thus, we have formulated working models for the role of host cell binding in colonization and disease expression by pathogenic Borrehae. To test predictions of these models, the following questions will be addressed: (1) does reducing the spirochete- platelet interactions affect colonization of the vessel wall and heart in Lyme disease or thrombocytopenia in relapsing fever? (2) does CD9 play a role in platelet activation by B. hermsii? (3) does the GAG-binding activity of the relapsing fever spirochete influence cell attachment and growth in the bloodstream of infected animals? (4) does Bgp play a predominant role in GAG binding by B. burgdorferi? The proposed experiments may uncover both potential therapeutic strategies for combating Borreliae infections as well as general principles that govern tissue-specific infection by bacterial pathogens.